Malaria parasite UIS3 (Upregulated in Infective Sporozoites gene 3) is essential for sporozoite development in infected hepatocytes. UIS3 encodes for a membrane protein which is localized to the parasite parasitophorous vacuolar membrane in infected hepatocytes. We describe here 2.5Å resolution crystal structure of Plasmodium falciparum UIS3 soluble domain (PfUIS^3130-229) in complex with the lipid phosphatidylethanolamine (PE). PfUIS^3130-229 is a novel, compact and all helical structure bound to one molecule of phosphatidylethanolamine (PE). The PfUIS^3130-229-PE complex structure reveals a novel binding site with specific interactions between PfUIS^3130-229and the PE head group. One acyl chain of PE wraps around part of PfUIS^3130-229and docks onto a hydrophobic channel. We additionally provide new structural and biochemical evidence of PfUIS^3130-229interactions with lipids (phosphatidylethanolamine), with phospholipid liposomes and with the human liver fatty acid binding protein (LFABP). The direct interaction of PfUIS^3130-229with LFABP most likely provides the parasite with a conduit for importing essential fatty acids/lipids. Therefore, our analyses have implications for lipid transport into the parasite during the rapid growth phases of sporozoites. Given that PfUIS3 is essential for establishment of liver stage infection by P. falciparum, our data provide a new target for abrogating parasite development within liver cells before typical symptoms of malaria can manifest.